Weekly paclitaxel as first-line chemotherapy and trastuzumab in patients with advanced breast cancer

Aim:to evaluate the activity and acute toxicity of thecombination of weekly paclitaxel as first-line chemotherapy andtrastuzumab, in patients with HER-2/neu overexpressing advanced breastcancer (ABC). Background:Weekly paclitaxel has beenshown to be a well tolerated treatment with considerable activity inpatients with ABC. Clinical trials with transtuzumab, a humanizedanti-p185 HER-2/neu monoclonal antibody have demonstrated that thisagent produces objective responses in patients with ABC. Patients and methods:From December 1998 to April 2000, 34patients with HER-2/neu overexpressing ABC were treated with weeklypaclitaxel; given by one-hour infusion at a dose of 90 mg/m²immediately followed by trastuzumab, 4 mg/kg as a loading dose and2 mg/kg i.v. given over 30 min, thereafter weekly for at least 12 weeks.Expression of HER-2/neu was determined by immunohistochemical analysison fixed, paraffin-embedded tissues. Eligible patients were required tohave 25% stained tumor cells. Results:Thirty-three patients completed at least 12 weeks of combinedtreatment. After completion of the 12th week of treatment, four patients(12%) achieved complete and 17 (50%) partial response.Median duration of response was 11.6 months. More frequent side effectsincluded anemia (56%), neutropenia (27%), peripheralneuropathy (78%), diarrhea (30%), alopecia (70%),arthralgias/myalgias (62%), fatigue (59%) andhypersensitivity reactions (62%). Median time to progression wasnine months while median survival had not been reached Conclusions:The combination of weekly paclitaxel andtrastuzumab is a safe and active regimen for patients with HER-2/neuoverexpressing ABC. Randomized phase III studies with this combinationare warranted.     

A phase II study of paclitaxel and capecitabine as a first-line combination chemotherapy for advanced gastric cancer

Paclitaxel and capecitabine, which have distinct mechanisms of action and toxicity profiles, have each shown high activity as single agents in gastric cancer. Synergistic interaction between these two drugs was suggested by taxane-induced upregulation of thymidine phosphorylase. We, therefore, evaluated the antitumour activity and toxicities of paclitaxel and capecitabine as first-line therapy in patients with advanced gastric cancer (AGC). Patients with histologically confirmed unresectable or metastatic AGC were treated with capecitabine 825 mg m(-2) p.o. twice daily on days 1-14 and paclitaxel 175 mg m(-2) i.v. on day 1 every 3 weeks until disease progression or unacceptable toxicities. Between June 2002 and May 2004, 45 patients, of median age 57 years (range=38-73 years), were treated with the combination of capecitabine and paclitaxel. After a median 6 cycles (range=1-9 cycles) of chemotherapy, 43 were evaluable for toxicity and response. A total of 2 patients showed complete response and 20 showed partial response making the overall response rate 48.9% (95% CI=30.3-63.5%). After a median follow-up of 42.2 months (range=31.2-54.3 months), median time to progression was 5.6 months (95% CI=3.9-7.2 months) and median overall survival was 11.3 months (95% CI=8.1-14.4 months). Grade 3 or 4 adverse events include neutropaenia (46.5% of patients), hand-foot syndrome (9.3%), arthralgia (9.3%), and asthenia (4.7%). There was no neutropaenic fever or treatment-related deaths. Paclitaxel and capecitabine combination chemotherapy was active and highly tolerable as a first-line therapy for AGC.     

TX方案治疗铂类治疗失败的进展期胃癌的临床疗效分析

目的：评价紫杉醇联合卡培他滨作为含铂类药物治疗失败的进展期胃癌二线治疗的疗效及安全性。方法：既往接受FP或者FOLFOX4方案化疗的进展期胃癌患者36例,采用TX方案化疗,紫杉醇145mg/m2静脉滴注3h,d1;卡培他滨2000mg/m2,分2次口服,d1-14,21天为一个周期,随访观察疗效,不良反应,进展时间和生存期。结果：36例患者共接受142个周期的化疗,中位化疗周期数4个。全组36例患者中有35例可评价疗效及不良反应,其中8例部分缓解,有效率为22.8%（95%CI：8.2%-37.5%）。中位进展时间和生存时间分别为4.8个月（95%CI：2.9-6.2）和8.1个月（95%CI：6.4-12.7）。Ⅲ/Ⅳ度不良反应主要为骨髓抑制、手足综合征及脱发。结论：紫杉醇联合卡培他滨方案二线治疗进展期胃癌疗效确切,不良反应小,尤其对老年患者耐受性好。     

TX方案治疗铂类治疗失败的进展期胃癌的临床疗效分析

目的:评价紫杉醇联合卡培他滨作为含铂类药物治疗失败的进展期胃癌二线治疗的疗效及安全性。方法:既往接受FP或者FOLFOX4方案化疗的进展期胃癌患者36例,采用TX方案化疗,紫杉醇145mg/m2静脉滴注3h,d1;卡培他滨2000mg/m2,分2次口服,d1-14,21天为一个周期,随访观察疗效,不良反应,进展时间和生存期。结果:36例患者共接受142个周期的化疗,中位化疗周期数4个。全组36例患者中有35例可评价疗效及不良反应,其中8例部分缓解,有效率为22.8%(95%CI:8.2%-37.5%)。中位进展时间和生存时间分别为4.8个月(95%CI:2.9-6.2)和8.1个月(95%CI:6.4-12.7)。Ⅲ/Ⅳ度不良反应主要为骨髓抑制、手足综合征及脱发。结论:紫杉醇联合卡培他滨方案二线治疗进展期胃癌疗效确切,不良反应小,尤其对老年患者耐受性好。     

Weekly paclitaxel as second-line chemotherapy for advanced or recurrent gastric cancer

Background Paclitaxel scheduled every 3 weeks has shown a response rate of ∼20% for gastric cancer, with modest hematological toxicity. Weekly administration of paclitaxel in patients with breast or ovarian cancer has shown equivalent efficacy and milder toxicity compared with an every-3 week schedule. We investigated, retrospectively, the antitumor effects and toxicity profiles of weekly paclitaxel for patients with metastatic or recurrent gastric cancer in clinical practice. Methods In 38 patients who had metastatic or recurrent histologically confirmed gastric cancer and a history of one prior chemotherapy regimen, other than paclitaxel or docetaxel, paclitaxel (8mg/m²) was administered weekly, three times every 4 weeks, with short-term premedication. Results All 38 patients had had prior chemotherapy that included 5-fluorouracil, the fluoropyrimidine anticancer drug S-1, or cisplatin. The median number of courses in the present regimen was 6 (range, 1–44+). Dose intensity was 5mg/m² per week, corresponding to 92% of the planned dose (6mg/m² per week). The overall response rate was 24% (6/25) in measurable lesions, and pleural effusion and ascites disappeared in 2 of 7 patients (29%) and in 3 of 21 patients (14%), respectively. Median survival time was 151 days from the commencement of this treatment, with a median follow-up period of 260 days. Grade 3 or 4 leukopenia and neutropenia were observed in 11 (29%) and 12 (32%) patients, respectively. Seven patients (18%) died within 30 days of the last administration of paclitaxel. Conclusion Weekly paclitaxel seems to be active as second-line chemotherapy against metastatic and recurrent gastric cancer. Further study is needed to confirm the efficacy and safety of weekly paclitaxel.     

Phase II trial of low-dose paclitaxel and cisplatin in patients with advanced gastric cancer

BACKGROUND: Paclitaxel has shown promising activity in gastric cancer and has synergism with cisplatin. This study was performed to evaluate the efficacy and toxicity of low-dose paclitaxel (145 mg/m(2)) plus cisplatin chemotherapy in metastatic or relapsed gastric cancer. METHODS: Chemotherapy-na?ve patients with metastatic or relapsed gastric cancer were enrolled. Paclitaxel 145 mg/m(2) was administered intravenously over 3 h, followed by cisplatin 60 mg/m(2) on Day 1 every 3 weeks in the outpatient setting. RESULTS: Of 39 patients enrolled, 17 (44%) had partial responses. Twelve (31%) had stable disease and eight (21%) progressive disease. Two patients (5%) were not evaluable because of early drop-out. The median time to progression was 4.7 months and the median overall survival was 12.1 months. The most common hematologic toxicity was anemia (41%). Grade 3/4 neutropenia and thrombocytopenia developed in 14 and 3%, respectively. The most common non-hematologic toxicities were peripheral neuropathy (43%) and emesis (43%). Grade 3/4 non-hematologic toxicities included emesis (11%), peripheral neuropathy (3%), diarrhea (3%) and hepatotoxicity (3%). CONCLUSIONS: Low-dose paclitaxel and cisplatin chemotherapy was active and well-tolerated in chemotherapy-na?ve gastric cancer patients. This regimen seems to have comparable efficacy to previously reported higher-dose paclitaxel plus cisplatin-containing regimens and fewer toxicities.     

紫杉醇联合希罗达治疗进展期胃癌

目的：评价紫杉醇联合希罗达治疗晚期胃癌的疗效及毒副反应。方法：22例进展期胃癌患者，应用紫杉醇80mg／m^2，d1,8希罗达1000mg／m^2，bid，d1-14，口服，每3周重复。结果：有效率（CR＋PR）59％（13／22），疾病进展时间6．5月，中位生存期11．4月，1年生存率43．5％，生活质量改善75％。主要不良反应为骨髓抑制，Ⅲ／Ⅳ度骨髓抑制27％，手足综合症47％，胃肠道反应42％，多为Ⅰ／Ⅱ度。结论：紫杉醇联合希罗达治疗进展期胃癌疗效好，不良反应可耐受。     

Randomised phase II study comparing dose-escalated weekly paclitaxel vs standard-dose weekly paclitaxel for patients with previously treated advanced gastric cancer

Background:

This randomised phase II trial compared dose-escalated weekly paclitaxel (wPTX) vs standard-dose wPTX for patients with previously treated advanced gastric cancer (AGC).

Methods:

Ninety patients were randomised to a standard dose of wPTX (80 mg m⁻²) or an escalated dose of wPTX (80–120 mg m⁻²) to assess the superiority of overall survival (OS) with a one-sided alpha error of 0.3 and a power of 0.8.

Results:

The median OS showed a trend towards longer survival in the dose-escalated arm (11.8 vs 9.6 months; hazard ratio (HR), 0.75; one-sided P=0.12), although it was statistically not significant. The median progression-free survival (PFS) was significantly longer in the dose-escalated arm (4.3 vs 2.5 months, HR, 0.55; P=0.017). Objective response rate was 30.3% with dose escalation and 17.1% with standard dose (P=0.2). The frequency of all grades of neutropenia was significantly higher with dose escalation (88.7% vs 60.0%, P=0.002); however, no significant difference was observed in the proportion of patients experiencing grade 3 or more (40.9% vs 31.1%, P=0.34).

Conclusion:

Dose-escalated wPTX in patients with pretreated AGC met our predefined threshold of primary end point, OS (P<0.3); however, it did not show a significantly longer OS. Progression-free survival was significantly better with dose escalation.     

单周方案紫杉醇单药治疗在晚期胃癌应用的进展

晚期胃癌给予化疗加支持治疗，患者的生存率和生活质量都较单独给予支持治疗高。目前，在晚期胃癌治疗中，紫杉醇类的药物是最有前途的细胞毒药物之一。紫杉醇的单药使用，特别是低剂量每周的单药治疗，显示出了令人振奋的作用，且毒副反应较低，起效快，迅速缓解症状，对于一些老年、生存状况差、不适于进行联合化疗，甚至失去常规化疗指征的晚期胃癌患者，不失为一种可供选择的治疗方法。本文着重介绍小剂量每周紫杉醇单药治疗晚期胃癌的一些临床报道。     

紫杉醇联合草酸铂治疗30例晚期胃癌

目的 研究联合紫杉醇及草酸铂两种新药用于治疗晚期胃癌，并评价此方案的近期疗效及其毒副作用。方法：对入选的30例晚期胃癌患者以紫杉醇联合草酸铂(单周或双周)方案予全身化疗，并配合每周1次顺铂(DDP)或氟嘧啶脱氧核苷(FUDR)单药腹腔灌注化疗。结果：30例胃癌患者平均化疗1．2个疗程，CR2例，PR17例，总有效率RR(CR PR百分率)为63％、(95％可信区间为46％～80％)。毒副反应主要为骨髓抑制，发生率达77％，但60％为Ⅰ-Ⅱ度，有3例(10％)为Ⅳ度；胃肠道反应、肝功损害、末梢神经炎、肾功损害、粘膜炎及心脏毒性发生率分别为40％、30％、13％、10％、10％及7％，大都为Ⅰ-Ⅱ度。所有患者均未因毒副作用中断或退出治疗。结论：紫杉醇联合草酸铂方案治疗晚期胃癌近期疗效是肯定的，毒副反应较轻，适合于对其他化疗反应大、有潜在心、肝、肾功不良或年老体弱、多次化疗后、恶性度高或急需减瘤考虑Ⅱ期手术的患者。     

紫杉醇联合氟尿嘧啶治疗青年进展期胃癌疗效观察

目的:观察紫杉醇联合氟尿嘧啶治疗青年进展期胃癌的临床疗效及不良反应。方法:86例经病理学证实青年Ⅲ-Ⅳ期胃癌患者,随机分为2组:紫杉醇组40例予紫杉醇联合亚叶酸钙及氟尿嘧啶,铂类组予奥沙利铂联合亚叶酸钙及氟尿嘧啶方案化疗,均化疗2个周期以上,每个周期28d。结果:紫杉醇组有效率50%,有末梢神经炎、血液学毒性,胃肠道反应率为25%。含奥沙利铂方案的有效率48%,有末梢神经炎、血液学毒性,胃肠道反应率为44%。2组有效率比较无显著性差异(P>0.05),胃肠道反应率比较有显著性差异(P<0.05)。结论:紫杉醇联合亚叶酸钙及氟尿嘧啶治疗青年进展期胃癌不良反应小,尤其是胃肠道不良反应较小,疗效确切,甚至可以代替铂类做为一线方案首选。     

紫杉醇联合氟尿嘧啶治疗青年进展期胃癌疗效观察

目的：观察紫杉醇联合氟尿嘧啶治疗青年进展期胃癌的临床疗效及不良反应。方法：86例经病理学证实青年Ⅲ-Ⅳ期胃癌患者,随机分为2组：紫杉醇组40例予紫杉醇联合亚叶酸钙及氟尿嘧啶,铂类组予奥沙利铂联合亚叶酸钙及氟尿嘧啶方案化疗,均化疗2个周期以上,每个周期28d。结果：紫杉醇组有效率50%,有末梢神经炎、血液学毒性,胃肠道反应率为25%。含奥沙利铂方案的有效率48%,有末梢神经炎、血液学毒性,胃肠道反应率为44%。2组有效率比较无显著性差异（P〉0.05）,胃肠道反应率比较有显著性差异（P〈0.05）。结论：紫杉醇联合亚叶酸钙及氟尿嘧啶治疗青年进展期胃癌不良反应小,尤其是胃肠道不良反应较小,疗效确切,甚至可以代替铂类做为一线方案首选。     

紫杉醇联合化疗方案治疗晚期胃癌的临床疗效

目的：观察国产紫杉醇（PTX,商品名为特素）联合国产草酸铂（OXA,商品名为艾恒）、亚叶酸钙（CF）、5-氟尿嘧啶（5-Fu）,治疗晚期胃癌的近期疗效及毒副反应。方法：选取病理检查证实的晚期胃癌患者24例,所有患者均有可评价病灶。治疗方案为：PTX60mg/m^2iv gtt d1,d8,d15;CF100mg/m^2,iv gtt d1-d5;5-Fu 375mg/m^2,iv gtt d1-d5;OXA65mg/m^2 iv gtt d1,d8。以上方案每28天为1周期,所有患者至少接受2周期治疗。结果：经2周期以上治疗后,CR2例,PR13例,NC5例,PD4例。总有效率62.5%,主要毒副反应为恶心、呕吐,骨髓抑制,脱发,外周神经感觉异常,肝肾功能轻度损害。结论：国产紫杉醇联合草酸铂,亚叶酸钙,5-氟尿嘧啶,治疗晚期胃癌疗效较好,毒副反应可耐受,值得临床推广应用。     

含紫杉醇的化疗方案治疗晚期胃癌的临床疗效观察

目的观察国产紫杉醇(特素)联合亚叶酸钙(CF),5-氟尿嘧啶(5-Fu),顺铂(DDP)治疗晚期胃癌的近期疗效及毒副反应。方法选取病理检查证实的晚期胃癌患者22例,所有患者均有可评价病灶。治疗方案为:特素60mg/m2iv gtt d1,8,15;CF 100mg/m2,iv gtt d1~5;5-Fu 375mg/m2,iv gtt d1~5;DDP 20mg/m2iv gtt d1~5。以上方案每28天为一周期,所有患者至少接受二周期治疗。结果经二周期以上治疗后,CR 1例,PR 12例,SD 6例,PD 3例。总有效率59.1%,主要毒副反应为恶心呕吐,骨髓抑制,脱发,感觉异常,肝肾功能轻度损害。结论国产紫杉醇联合亚叶酸钙,5-氟尿嘧啶,顺铂治疗晚期胃癌疗效较好,不良反应可耐受。     

奥沙利铂联合卡培他滨一线治疗进展期胃癌的临床疗效观察

背景与目的：奥沙利铂联合卡培他滨（XELOX方案）是治疗进展期胃癌（advanced gastric cancer,AGC）的有效方案,但是该方案作为一线方案治疗AGC患者的疗效和安全性尚不确定。本研究旨在探讨XELOX方案作为一线方案治疗AGC的疗效及安全性。方法：33例既往未接受过化疗的AGC患者采用XELOX方案化疗．奥沙利铂130mg／m^2,静脉滴注2h,d1;卡培他滨2000mg／m^2,分2次口服．d1～14,21天为一个周期。患者最多接受8个周期化疗。结果：33例患者共接受159个周期的化疗,中位化疗周期数为5个。31例患者可评价疗效,其中完全缓解1例（3．2％）,部分缓解16例（51．6％）,稳定8例（25．8％）,进展6例（19．4％）。客观有效率54．8％（95％可信区间37．3％-72．3％）,临床获益率80．6％（95％可信区间66．7％～94．5％）。平均随访10．5个月,中位疾病进展时间5．9个月（95％可信区间4．7～7．1个月）,中位生存时间10．4个月（95％可信区间7．9～12．9个月）。常见不良反应有骨髓抑制、外周神经毒性、胃肠道反应、手足综合征等,经对症治疗后均好转．无治疗相关性死亡。结论：XELOX方案一线治疗AGC疗效显著,耐受性良好。     

Phase I/II study of S-1 combined with paclitaxel in patients with unresectable and/or recurrent advanced gastric cancer

Both paclitaxel and S-1 are effective against gastric cancer, but the optimal regimen for combined chemotherapy with these drugs remains unclear. This phase I/II study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD), dose-limiting toxicity (DLT), and objective response rate of paclitaxel in combination with S-1. S-1 was administered orally at a fixed dose of 80 mg m-2 day-1 from days 1 to 14 of a 28-day cycle. Paclitaxel was given intravenously on days 1, 8, and 15, starting with a dose of 40 mg m-2 day-1. The dose was increased in a stepwise manner to 70 mg m-2. Treatment was repeated every 4 weeks unless disease progression was confirmed. In the phase I portion, 17 patients were enrolled. The MTD of paclitaxel was estimated to be 70 mg m-2 because 40% of the patients given this dose level (two of five) had DLT. The RD was determined to be 60 mg m-2. In the phase II portion, 24 patients, including five with assessable disease who received the RD in the phase I portion, were evaluated. The median number of treatment courses was six (range: 1-17). The incidence of the worst-grade toxicity in patients given the RD was 28 and 8%, respectively. All toxic effects were manageable. The response rate was 54.1%, and the median survival time was 15.5 months. Our phase I/II trial showed that S-1 combined with paclitaxel is effective and well tolerated in patients with advanced gastric cancer.     

培美曲塞联合奥沙利铂方案和紫杉醇脂质体联合替吉奥方案二线治疗晚期胃癌的临床研究

目的:观察培美曲塞联合奥沙利铂方案和紫杉醇脂质体联合替吉奥方案在晚期胃癌二线治疗中的近期疗效和安全性。方法:经病理组织学或细胞学确诊的60例晚期胃癌患者随机分为两组,A组28例(培美曲塞500mg/m2 iv d1,奥沙利铂85mg/m2 iv d1),B组32例(紫杉醇脂质体135mg/m2 iv d1,替吉奥40mg/m2 bid d1~14),21天为1周期,2周期后评价疗效及不良反应发生情况。结果:60例患者均可评价疗效,Ａ组和Ｂ组有效率分别是14.29％和18.75％(P＞0.05),疾病控制率分别是46.43％和56.25％(P＞0.05),中位TTP分别为5.8个月和6.2个月(P＞0.05)。化疗不良反应总体上均可耐受,A组乏力、皮疹和脱发发生率为78.57%、35.71%和25.0%(P＜0.05),B组白细胞减少、血小板减少发生率分别为68.75%和62.50%(P＜0.05)。结论:培美曲塞联合奥沙利铂方案和紫杉醇脂质体联合替吉奥方案二线治疗晚期胃癌的近期疗效相当,不良反应可耐受,可以作为晚期胃癌的有效姑息治疗方案。     

紫杉醇联合顺铂及5-氟尿嘧啶治疗进展期胃癌的临床观察

目的：观察紫杉醇（PTX）联合顺铂（CDDP）及5-氟尿嘧啶（5-Fu）方案（PCF方案）治疗进展期胃癌的近期疗效及不良反应.方法：选取病理检查证实的晚期胃癌患者36例,所有患者均有可评价病灶.化疗方案为：PTX 175mg/m2 ivgtt d1;CDDP 20mg/m 2,ivgtt d1-5;5-FU 750mg/m2,ivgtt24h d1-5.28天为1周期,所有患者至少接受2周期化疗.结果：36例患者均完成2个周期以上化疗,总有效率为61.1%,其中完全缓解（CR）3例,部分缓解（PR）19例,疾病稳定（NC）8例,疾病进展（PD）6例.生存期为5个月-24个月,中位生存期为11.5个月.主要不良反应为恶心、呕吐、腹泻和血白细胞、血红蛋白及血小板减少,其中Ⅲ度-Ⅳ度白细胞减少9人（25.0%）,其余大部分反应为Ⅰ度-Ⅱ度,无化疗相关死亡病例.结论：紫杉醇联合顺铂、5-氟尿嘧啶化疗方案治疗进展期胃癌疗效较好,不良反应可耐受.     

氟尿嘧啶/亚叶酸联合奥沙利铂或紫杉醇治疗晚期胃癌--临床随机对比研究

目的：比较氟尿嘧啶／亚叶酸(5-FU／FA)联合奥沙利铂与5-FU／FA联合紫杉醇治疗晚期胃癌的近期疗效和毒副反应。方法：40例进展期胃癌患者随机分成两组，5-FU／FA联合奥沙利铂组(A组)20例，70．0％为复治患者，5-FU／FA联合紫杉醇组(B组)20例，55．0％为复治患者，转移部位包括肝、淋巴结、腹腔、腹壁等。结果：两组患者各有20例可评价疗效，A组CR2例，PR7例，有效率(CR PR)45．0％，B组PR9例，有效率45．0％。A组有20例评价毒性反应，主要为骨髓抑制、外周神经毒性、消化道反应、肝功能损害；B组有20例可评价毒性反应，主要为骨髓抑制、肝功能损害。结论：5-FU／FA联合奥沙利铂与联合紫杉醇治疗晚期胃癌疗效相当．毒性反应可耐受。两者相比，联合奥沙利铂具有用药方便，严重的毒副反应少等优点。     

Weekly paclitaxel for a patient with advanced gastric cancer

2 of paclitaxel, along with premedication for 3 weeks, followed by 1 week of rest, was started. After the first of these 4-week courses, the discharge from her nasogastric tube decreased to 200–600 ml per day, and the tube was removed 78 days after insertion. Oral intake of food increased smoothly, and she was discharged on September 14. After another, short, hospitalization, she was discharged on October 20, and she has been coming to our outpatient clinic once a week. After paclitaxel was started, gastric fiberscopy and computed tomography (CT) scan showed reduction of the tumor. Of special note was the disappearance of ascitic fluid after two courses, rated as a “partial response” (Japanese classification). There was a decrease in hemoglobin, but neither leukocytopenia nor a decrease in platelets was found. Neuropathy was slight and no treatment was needed. Now, after 1 year, 11 courses of chemotherapy have been administered at the outpatient clinic. These results suggest weekly administration of paclitaxel to be a promising treatment for advanced gastric cancer with peritoneal dissemination. The therapeutic efficacy should be confirmed by further clinical trials. Received: September 9, 2002 / Accepted: February 5, 2003 RID="*" ID="*" Offprint requests to: S. Yamamoto